Pharmacokinetics and Pharmacodynamics in Space

The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic regimens

Simulated Clinical Trias: some design issues

Simulation is widely used to investigate real-world systems in a large number of fields, including clinical trials for drug development, since real trials are costly, frequently fail and may lead to serious side effects. This paper is a survey of the statistical issues arising in these simulated trials. We illustrate the broad applicability of this investigation tool by means of examples selected from the literature. We discuss the aims and the peculiarities of the simulation models used in this context, including a brief mention of the use of metamodels. Of special interest is the topic of the design of the virtual experiments, stressing similarities and differences with the design of real life trials. Since it is important for a computerized model to possess a satisfactory range of accuracy consistent with its intended application, real data provided by physical experiments are used to confirm the simulator : we illustrate validating techniques through a number of examples. We end the paper with some challenging questions on the scientificity, ethics and effectiveness of simulation in the clinical research, and the interesting research problem of how to integrate simulated and physical experiments in a clinical context.Simulation models; pharmacokinetics; pharmacodynamics; model validation; experimental design, ethics. Modelli di simulazione; farmacocinetica; farmacodinamica; validazione; disegno degli esperimenti; etica.

Optimization of Lead Spectinamide Compounds as Novel Anti-tuberculosis Agents with a Pharmacometric Approach

In an effort to combat the global Tuberculosis pandemic, Dr.Richard E. Lee and his group at St.Jude Children’s Research Hospital designed a novel series of anti-tuberculosis agents, spectinamides – semi-synthetic analogs of spectinomycin. Spectinamides are a potent inhibitor of mycobacterial ribosomes and overcome efflux mediated drug resistance in M. tb. Spectinamides have shown an excellent in vitro activity, which makes them well suited for further lead optimization and preclinical development. We hypothesized that through pharmacokinetic (PK) and pharmacodynamics (PD) model-based dosing optimization studies, we could strategically guide the selection and refinement of more potent and effective anti-TB spectinamides. Biopharmaceutical in vitro screening demonstrated that spectinamides in general have low plasma protein binding and are stable against hepatic microsomal metabolism. In vivo pharmacokinetic studies in rats revealed that the kidneys are the major route of elimination for spectinamides in their unchanged form. Radiolabeled biodistribution studies showed 84.7% of radioactivity accumulated 70% in urine, 12.6% in feces, and the remainder in the blood and other major organs. The unaccounted for residual 15.3% likely distributed into the epidermis and other surface tissue. In multiple-dose accumulation studies, the Cmax of radiolabeled compound after the 1st dose and the 8th dose of twice-daily dosing regimen was similar: 3.39µCi/mL and 3.55µCi/mL, suggesting no relevant accumulation of parent drug and metabolites. The concentration of radiolabeled compound was three times more in lungs and spleen as compared to whole blood, suggesting good tissue penetration. Macrophage uptake studies showed that Lee 1329, Lee1445 and Lee 1599 had significantly higher macrophage uptake than spectinomycin and streptomycin. Lee 1329 showed 6-fold and 2.2-fold higher uptake than streptomycin and spectinomycin, respectively. Based on the results of the in vitro experiments and preliminary PK/PD studies in rats, Lee 1599 was selected as the lead candidate compound. To predict PK/PD indices of antimicrobial efficacy, we performed model-based dosing optimization studies with Lee 1599. We used an in vitro PK/PD model system to simulate the rat PK conditions while evaluating antibacterial activities to predict effective dosing regimens for further in vivo efficacy studies. Our results have shown that Lee 1599 exhibits dose-dependent bactericidal effect. Lee 1599 showed up to 4-log reductions in bacterial counts at 100mg QD dosing. The PK/PD indices demonstrated that Lee 1599 elicits a concentration- and time-dependent killing with AUC/MIC as the optimal index. The model was put through numerical simulations to predict the effect of Lee 1599 in mice at various dosing regimens. The in vitro PK/PD simulated profile has suggested that high doses with frequent dosing intervals may demonstrate optimum in vivo efficacy. Consequently, we aimed to determine the pharmacodynamic interaction between Lee 1599 and existing anti-tuberculosis agent. We selected rifampicin as a model compound and applied a parametric approach to quantitatively assess the pharmacodynamic drug interaction between Lee 1599 and rifampicin. The three dimensional surface response assay demonstrated that there is an additive effect between both the agents as opposed to the conventional checkerboard assay, which suggested synergism between these agents. The results of surface response assay were validated using an in vitro PK/PD model for combination agents and in vivo efficacy trials, which showed an additive effect between Lee 1599 and rifampicin. Thus, quantitative assays such as the surface response assay seem to provide more reliable information on pharmacodynamic interactions as opposed to qualitative methods such as checkerboard assay. In conclusion, we have successfully supported the further development of spectinamides using a pharmacometric approach. We have identified a lead candidate compound Lee 1599 using an iterative PK/PD approach for its pre-clinical drug development. The application of PK/PD knowledge is essential for translating the in vitro screening assay findings to the in vivo stage, thus accelerating the drug development process. The results of the above studies can be used as a roadmap for the optimization of anti-infective agents in the early drug discovery and pre-clinical developmental phase

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation in the Development of Spectinamides, a Novel Class of Anti-Tuberculosis Agents

New chemotherapeutic agents are urgently needed to control the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of tuberculosis, which still remains an important public health challenge globally. Recently, spectinamides have emerged as a novel class of anti-tuberculosis agents that overcomethe native drug efflux. Spectinamides bind to the 30S bacterial ribosomal subunit which interferes with ribosomal translocation, and ultimately results in inhibition of protein synthesis. They have potent in vitro activity against drug resistant Mycobacterium tuberculosis (Mtb), and also demonstrated sustained efficacy in (Mtb)-infected mouse models. Pharmacokinetic (PK)/ pharmacodynamic (PD) analyses play a critical role in identifying the optimum dosing regimen for new treatments. In this dissertation, I hypothesized that the application of translational PK/PD modeling and simulation techniques would facilitate rational dosage regimen design for spectinamides. To characterize the dose-exposure-response of Lee 1810, a dose-fractionation study was performed in BALB/c mice infected with a low dose aerosol of (Mtb). Dosing with different dosing regimens was continued for 4 weeks with two blood samples obtained from each mice in the last week, followed by a washout period after which the mice were sacrificed and the lungs removed for measurement of colony forming units (CFU). Drug concentrations in plasma were analyzed with a validated LC-MS/MS method followed by a population PK analysis which also included as anchor point the data of a PK study in healthy mice with intensive sampling. A model for natural bacterial growth in Mtb infection in untreated mice was built from data on the natural history of Mtb infection in mice obtained from previously performed studies and from the literature. Based on the individual post hoc estimates from the population PK modeling, a sequential PK/PD analysis was performed by linking the PK model with the bacterial growth model via an exposure-dependent bacterial kill function that included a sigmoid Emax model for describing the overall rate of change in lung CFU with different dosing regimens. A two-compartment model with first-order absorption was used to describe the pharmacokinetics of Lee 1810. The average absorption rate constant (Ka), clearance (CL/F), volume of the central compartment (Vc/F), intercompartmental clearance (Q/F), and volume of the peripheral compartment (Vp/F) was estimated to be 2.31 h-1,1.17 L/h/kg, 0.435 L/kg, 0.0191 L/h/kg, and 0.161 L/kg, respectively. The inter-individual variability in CL/F was estimated as 19.9 %. The pharmacokinetics of Lee 1810 was found to be different between healthy and infected mice with the later having 56.5% lower CL/F, 69% lower Vc/F and 69.6% lower Q/F. The two-subpopulation model could successfully describe the natural bacterial growth. The replication rate constant (Krep) of Mtb was calculated as 0.0327 h-1 which is consistent with values reported in the literature. The death rate constant induced by the immune system (Kir) was 0.00303 h-1, cell countof fast growing population at the initiation of the infection (N1,0) was 1.93 Log CFU and maximum number of bacteria (Nmax) was 6.44 Log CFU. The inter-individual variability in Krep and Nmax was estimated as 70.8 % and 54.7%, respectively. The bacterial kill induced by the drug was described using a sigmoid Emax model. The drug effect parameters (EC50), maximum kill rate (Emax) and Hill coefficient (y), were estimated as 239 μg/mL, 11.9 h-1 and 2.40 respectively. A Hill coefficient substantially greater than 1 is a typical characteristic of concentration-dependent killing. The concentration dependent killing characteristic of Lee 1810 supports its intermittent dosing. Poor permeability of spectinamides across the gut limits its oral use. Additionally, since the lungs are the main site of infection in pulmonary TB, the efficacy of lead spectinamide Lee 1599 was evaluated after intratracheal (IT) administration in a mouse model of Mtb infection. A dose of 200 mg/kg TIW (3 days a week) for 28 days resulted in excellent efficacy with 2.2 Log CFU reduction in the lungs. Based on these observations, a comparative biodistribution study of Lee 1599 was performed after IT and SC administration in mice. Plasma and tissue samples were collected at pre-specified time points. The drug was extracted from plasma and homogenized tissues after protein precipitation and analyzed with an LC-MS/MS assay. The rate and extent of absorption was almost two times higher with IT as compared to SC administration. As expected, the highest exposure of Lee 1599 after IT administration was attained in the lungs, which was 2.5 times higher than in plasma. This is highly desirable as lungs are the main site of infection in pulmonary tuberculosis. Overall, this study supports the pulmonary route as a potential pathway for the treatment of tuberculosis with Lee 1599. Physiologically-based pharmacokinetic (PBPK) modeling and simulation is a powerful methodology used in support of dose selection for first-in-human studies. The objective was to develop a PBPK model for describing pharmacokinetics of Lee 1599 in rats and mice, and to extrapolate this PK behavior to humans. 10 mg/kg of Lee 1599 was administered intravenously to rats and 200 mg/kg subcutaneously to mice. The PBPK model was developed based on the observed rat plasma concentrations, physicochemical properties of Lee 1599, and in vitro data from its metabolism, protein binding and permeability. The concentration-time profile of Lee 1599 in rats was well described by the optimized PBPK model. The model was prospectively qualified by PBPK scaling from rats to mice and comparing predicted murine concentration-time profiles to observed plasma concentrations. This model was also successful in predicting murine PK with observed PK parameters within two-folds of predicted values. The model predicted, weight normalized human clearance of 0.25 L/h/kg was as expected less than the values in rats (0.666 L/h/kg) and mice (1.25 L/h/kg). The PBPK model predicted, a dose of 7.5 mg/kg and 27.5 mg/kg administered once daily via intravenous administration will be required to attain similar exposure as observed in mice after subcutaneous administration of 50 mg/kg and 200 mg/kg respectively. This model suggests that an efficacious systemic exposure can be achieved with daily doses feasible in humans, and may be useful during drug development for understanding the dose requirements for future human studies. In conclusion, translational PK/PD approaches have been successfully used for the further development and characterization of spectinamides leads Lee 1599 and Lee 1810. The results from the above studies will be helpful in identifying and optimizing the dosing regimens which can strike a balance between bacterial reduction, adverse effects, and emergence of resistance

In vitro and in silico approaches to evaluate the pharmacokinetics and pharmacodynamics of combination antibiotic therapy against drug-resistant bacteria

This thesis focuses on combating antibacterial resistance by developing novel in vitro and in silico techniques. In vitro techniques such as in vitro pharmacodynamic (IVPD) modeling are powerful tools for investigating pharmacokinetic and pharmacodynamic response of antibiotics against bacteria. The standard IVPD model in the literature works for simulating monotherapy and combination therapy of drugs having similar half live. But it does not work for combination therapy of drugs having different half live. The method present in the literature for combination therapy of drugs with different half live was described by Blaser. By utilizing Blaser’s method, it was observed that the concentration of drug having a longer half-life could not be achieved as expected in vivo. Therefore, it was essential to develop a novel in vitro pharmacodynamic model to address this limitation. The novel IVPD model in this thesis has overcome this issue by varying the infusion rate at which the drug with longer half-life was being supplemented to the central vessel. The change in infusion rate was calculated to mimic the in vivo plasma concentration of the longer half-life drug. The novel IVPD model was verified by running a 48 hour experiment where the concentration of drug with longer half-life (ceftriaxone) was monitored. Another aspect of this research was dedicated to developing a physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model for combination therapy of amicrobial medications acting synergistically (ampicillin and ceftriaxone). PBPK modeling is a dynamic method that predicts in vivo systemic drug exposure in humans based on the compound’s physicochemical properties and absorption, distribution, metabolism and excretion (ADME) characteristics. Interlinking it with the pharmacodynamic model would help to understand the change in pharmacodynamic response caused due to alterations in the pharmacokinetics of drug that impact systemic exposure. An advantage of developing PBPK-PD model for combination therapy is it can act as a predictive tool to optimize dosing regimen and understand the pharmacodynamic response in special populations (renal impaired patients, pediatrics, pregnant women, etc.). To develop the PBPK-PD model, substrate profiles for ampicillin and ceftriaxone were first created and verified in healthy volunteers against published literature. Verification was performed by visual predictive check and by calculating the fold error for maximum concentration (Cmax) and area under the curve (AUC). A custom PD model was developed using lua script code which can simulate a pharmacodynamic response for drugs acting synergistically. The PBPK model was interlinked with the PD model. The PBPK-PD model was verified against in vitro results published in the literature. The PD end point was the observed decrease in bacterial count over a period of 72 hours. A dosing regimen of ampicillin 2g q 4 hours and ceftriaxone 2g q 12 hours was simulated using the PBPK-PD model. It was observed that the PBPK-PD model developed in this research could capture the in vitro pharmacodynamic experiment data. Once verified, the PBPK-PD model was extended to a population of severe renal impaired patients. PBPK-PD model was used to justify the change in dose frequency of ampicillin when given in combination with ceftriaxone in severe renal impaired patients’ population. Two dosing regimens were simulated in severe renal impaired patients: 1) ampicillin 2g q 8 hours and ceftriaxone 2g q 12 hours, and 2) ampicillin 2g q 6 hours and ceftriaxone 2g q 12 hours. In a patient population with renal impairment a regimen comprised of ampicillin IV 2000 mg every q-6 hours and ceftriaxone IV 2000 mg q-12 hours achieved complete eradication of bacteria. The novel PBPK-PD model created in this dissertation research is of clinical significance as an in silico approach can be used to optimizing dosing regimens in special patient populations being treated with a combination of antimicrobial drugs acting synergistically

Simulated Clinical Trias: some design issues

Simulation is widely used to investigate real-world systems in a large number of fields, including clinical trials for drug development, since real trials are costly, frequently fail and may lead to serious side effects. This paper is a survey of the statistical issues arising in these simulated trials. We illustrate the broad applicability of this investigation tool by means of examples selected from the literature. We discuss the aims and the peculiarities of the simulation models used in this context, including a brief mention of the use of metamodels. Of special interest is the topic of the design of the virtual experiments, stressing similarities and differences with the design of real life trials. Since it is important for a computerized model to possess a satisfactory range of accuracy consistent with its intended application, real data provided by physical experiments are used to confirm the simulator: we illustrate validating techniques through a number of examples. We end the paper with some challenging questions on the scientificity, ethics and effectiveness of simulation in the clinical research, and the interesting research problem of how to integrate simulated and physical experiments in a clinical context

The role of Pharmacometrics in the development of Cuban Biotechnology products

Pharmacometrics is a vibrant scientific discipline that involves a cycle of excellence: integration, innovation and impact. This work was aimed to assess different pharmacometric approaches in three Cuban biotechnological products. A population pharmacokinetic analysis of nimotuzumab was performed in patients with stage III breast cancer with different doses of it, in combination with doxorubicin and cyclophosphamide. The pharmacokinetic/pharmacodynamic (PK/PD) characterization of Pegylated Recombinant Human Erythropoietin (rHuEPO) branched 32 kDa-PEG-rHuEPO and 40 kDa- PEG-rHuEPO was conducted and compared with reference products (ior®EPOCIM and MIRCERA®) in New Zealand rabbits. Data were analyzed using the nonlinear mixed-effect approach (NONMEM®). The best model for nimotuzumab was the Quasi Steady State approximation of the full Target Mediated Drug Disposition model that best described the linear and nonlinear PK. The recommended optimal biological dose ranged between 200-400mg/ week. On the other hand, a cell transit semi-mechanistic PK/PD model for characterizing rHuEPO profiles was obtained. The development of new branched PEG-chain formulations of rHuEPO improves its PK and PD properties, compared to those of commercially available formulations (i.e., ior®EPOCIM and MIRCERA®). Due to its integrative nature and predictive value, population modeling was very useful in the optimal characterization of the pharmacokinetic and pharmacodynamic properties of these three Cuban biotech drug products. It had a significant impact on decisionmaking by both the national regulatory agency and the local biopharmaceutical industry as to their research and development plans, as well as the subsequent marketing strategies for these new products, with substantial economic and time saving benefits. This work received the Annual Award of the Cuban Academy of Sciences for the year 2019

Readings in Advanced Pharmacokinetics

This book, “Readings in Advanced Pharmacokinetics - Theory, Methods and Applications”, covers up to date information and practical topics related to the study of drug pharmacokinetics in humans and in animals. The book is designed to offer scientists, clinicians and researchers a choice to logically build their knowledge in pharmacokinetics from basic concepts to advanced applications. This book is organized into two sections. The first section discusses advanced theories that include a wide range of topics; from bioequivalence studies, pharmacogenomics in relation to pharmacokinetics, computer based simulation concepts to drug interactions of herbal medicines and veterinary pharmacokinetics. The second section advances theory to practice offering several examples of methods and applications in advanced pharmacokinetics